calcitriol and Arthritis--Rheumatoid

From time to time there have been reports of autoimmune disease succumbing to tetracycline antibiotics, but many have assumed this was due to coincidence, or to some ill-defined 'anti-inflammatory property' of the tetracyclines. But now the inflammation of sarcoidosis has succumbed to antibiotics in two independent studies. This review examines the cell wall deficient (antibiotic resistant) bacteria which have been found in tissue from patients with sarcoidosis. It examines how such bacteria can infect the phagocytes of the immune system, and how they may therefore be responsible for not only sarcoid inflammation, but also for other autoimmune disease. Proof positive of a bacterial pathogenesis for Sarcoidosis includes not only the demonstrated ability of these studies to put the disease into remission, but also the severity of Jarisch-Herxheimer shock resulting from endotoxin release as the microbes are killed. Studies delineating the hormone responsible for phagocyte differentiation in the Th1 immune response, 1,25-dihydroxyvitamin D, are discussed, and its utility as a marker of Th1 immune inflammation is reviewed. Finally, data showing that the behavior of this hormone is also aberrant in rheumatoid arthritis, systemic lupus erythematosus, and Parkinson's, raise the possibility that these diseases may also have a CWD bacterial pathogenesis.

Topics: Animals; Anti-Bacterial Agents; Arthritis, Rheumatoid; Autoimmune Diseases; Bacteria; Doxycycline; Forecasting; Humans; Lupus Erythematosus, Systemic; Minocycline; Parkinson Disease; Phagocytes; Sarcoidosis; Secondary Prevention; Tetracyclines; Vitamin D

1,25 dihydroxy vitamin D3 has immunomodulatory functions in rheumatoid arthritis (RA) and is an anti-osteoporotic agent. No studies exist to assess its pain-relieving action in RA.. An open-labeled randomized trial comparing triple disease-modifying anti-rheumatic drug (DMARD) therapy and 500 IU 1,25 dihydroxy vitamin D3 + calcium combination versus triple DMARD and calcium alone was conducted. The primary outcome was the time to pain relief by patients' visual analogue scale (VAS). Changes in VAS after first achievement of pain relief and after 3 months were noted. 25 hydroxy-vitamin D levels were correlated with disease activity scor (DAS-28), adjusting for sun exposure. Comparisons between the groups were done by Mann-Whitney test and independent samples test.. Patients on the vitamin D group (n = 59) had higher pain relief than the control group (n = 62) (50%vs. 30%, P = 0.006). There was no significant difference in the time taken for initial pain relief between the two groups. Occurrence of hypovitaminosis D in RA patients (68.1%) is comparable to published normal Indian prevalence. There was no correlation between 25 hydroxy vitamin D levels and disease activity.. Supplementation of 500 IU of 1,25 dihydroxy vitamin D3 daily to previously DMARD-naïve patients with early RA along with triple DMARD therapy results in a significantly higher pain relief at the end of 3 months. The number needed to treat for this additional pain relief was 5. The prevalence of vitamin D deficiency in the study population was 68.1%.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Calcium, Dietary; Dietary Supplements; Drug Therapy, Combination; Early Diagnosis; Female; Health Status; Humans; Male; Middle Aged; Pain; Severity of Illness Index; Treatment Outcome; Vitamin D

Topics: Animals; Arthritis, Rheumatoid; Dihydroxycholecalciferols; DNA-Binding Proteins; eIF-2 Kinase; Interleukin-6; Macrophage Activation; Mice; Mice, Transgenic

Immune cells express the vitamin (vit) D receptor, and vit D is a potent immune-modulator. A negative correlation between serum vit D levels and rheumatoid arthritis (RA) disease activity has been reported. Therefore, we aimed to investigate if the sufficient serum vit D level is helpful to control disease activity in RA patients treated with interleukin (IL)-6 receptor antibody tocilizumab.. RA patients taking tocilizumab were enrolled, and data were collected retrospectively. Disease activity scores (DAS) 28, serum vit D levels, modified Sharp scores of hand X-ray at the time of tocilizumab initiation, and follow-up data were analysed. Peripheral blood mononuclear cells were differentiated into T-helper (Th) 17 or osteoclasts in the presence of various concentrations of tocilizumab and/or 1,25(OH)₂D. Th17 proportions were analysed by fluorescence-activated cell sorting. Supernatant cytokine levels were determined by enzyme-linked immunosorbent assay.. Among 98 RA patients taking tocilizumab, 34 (34.7%) had sufficient serum 25(OH)D levels (≥ 30 ng/mL) when tocilizumab was initiated. At 24 weeks, vit D sufficient patients had greater DAS28 reduction (64.6% ± 15.5% vs. 52.7% ± 20.7%,. RA patients treated with IL-6 antibody show a better response when they have sufficient serum vit D. Tocilizumab and 1,25(OH)₂D synergistically suppress IL-17 production and osteoclast differentiation in RA patients.

Topics: Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Leukocytes, Mononuclear; Osteogenesis; Receptors, Interleukin-6; Retrospective Studies; Vitamin D

This study is to investigate the additive effect of Vitamin D-binding protein (VDBP) and 1,25(OH)2D3 on the viability and apoptosis of synovial cells from patients with rheumatoid arthritis (RA).. Synovial tissues and synovial fluid of patients with RA and osteoarthritis (OA) were collected. The expression of VDBP was analyzed with immunohistochemistry and ELISA. CCK-8 assay was applied to detect cell viability. Flow cytometry was used to analyze cell cycle and apoptosis.. Immunohistochemical results showed that the expression of VDBP in the synovium of RA patients was significantly lower than that of OA (P<0.05). Similarly, ELISA results presented a lower expression of VDBP in the synovial fluid of RA patients. The results of CCK-8 assay showed that both 1,25(OH)2D3 and VDBP significantly inhibited the viability of rheumatoid arthritis synovial fibroblasts (RASF) (P<0.05). The treatment with 1,25(OH)2D3+VDBP led to more significantly inhibited viability of RASF, compared with 1,25(OH)2D3 alone (P<0.05). The results of flow cytometry showed that 1,25(OH)2D3 and VDBP both promoted the apoptosis of RASF (P<0.05) and 1,25(OH)2D3+VDBP led to a higher proportion of RASF apoptosis, compared with 1,25(OH)2D3 alone (P<0.05). However, 1,25(OH)2D3 and VDBP had no significant effect on the cell cycle of RASF. Additionally, 1,25(OH)2D3 promoted the expression of VDBP in RASF, but not concentration-dependently.. VDBP is reduced in the synovial tissue and synovial fluid of RA patients and can inhibit viability of RASF and promote the apoptosis of RASF. The 1,25(OH)2D3 can upregulate the expression of VDBP in RASF. Additionally, VDBP can enhance the effects of 1,25(OH)2D3 on viability and apoptosis of RASF.

Topics: Aged; Apoptosis; Arthritis, Rheumatoid; Case-Control Studies; Cell Cycle; Cell Proliferation; Cells, Cultured; Combined Modality Therapy; Female; Fibroblasts; Gene Expression Regulation; Humans; Male; Middle Aged; Osteoarthritis; Synoviocytes; Vitamin D; Vitamin D-Binding Protein

An aggressive proliferation of synoviocytes is the hallmark of rheumatoid arthritis (RA). Emerging evidence shows that inhibiting the NF-κB signaling pathway with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] may be a therapeutic approach for controlling inflammatory diseases. In this study, we demonstrated the protective effects of three different 1,25(OH)2D3 concentration on adjuvant-induced arthritis (AA) rats through the NF-κB signaling pathway and their pro-apoptotic roles in cultured adjuvant-induced arthritis synoviocytes (AIASs). AA rats were prepared by injecting complete Freund's adjuvant and independently given daily intraperitoneal injection of 1,25(OH)2D3 at concentrations of 50, 100, and 300 ng/day/kg. Subsequently, AIASs were isolated from the inflamed joints of AA rats to test the effects of 1,25(OH)2D3 on AIASs in vitro. Intraperitoneal injection of 1,25-(OH)2D3 was found to induce a concentration- and time-dependent improvement in relieving the symptoms of AA. We found an increased paw withdrawal thermal latency (PWTL) in the affected paw of AA rats as the concentration of 1,25-(OH)2D3 increased. 1,25-(OH)2D3 treatment reduced levels of inflammatory factors in synovial tissues of AA rats. In the case of cultured AIASs, 1,25-(OH)2D3 was shown to inhibit cell proliferation and induce cell apoptosis in a concentration-dependent manner. Additionally, 1,25-(OH)2D3 inhibited the activation of the NF-κB signaling pathway. In conclusion, our study provides evidence emphasizing that 1,25(OH)2D3 has the potential to attenuate disease severity in RA potentially due to its contributory role in synoviocyte proliferation and apoptosis. The protective role of 1,25(OH)2D3 against RA depends on the NF-κB signaling pathway.

Topics: Animals; Apoptosis; Arthritis, Experimental; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Down-Regulation; Hyperplasia; Inflammation; Inflammation Mediators; Male; NF-kappa B; Rats, Sprague-Dawley; Severity of Illness Index; Signal Transduction; Synovial Membrane; Synoviocytes; Vitamin D

To investigate the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)₂D₃] on T helper cell type 17 (Th17) cytokines and therapeutic mechanism in patients with rheumatoid arthritis (RA).. Peripheral blood mononuclear cells (PBMCs) from healthy donors and RA patients were collected. The PBMCs were stimulated with anti-CD3/anti-CD28 monoclonal antibodies in the absence or presence of 1,25(OH)₂D₃and methotrexate (MTX). After co-culture, the serum levels of Th17 cytokines interleukin (IL)-17, IL-6, tumour necrosis factor alpha (TNFα) were analyzed by cytometric bead array (CBA). The level of IL-22 was analyzed by enzyme-linked immunosorbent assay (ELISA). The independent samples t test and one-way analysis of variance (ANOVA) were used for statistical analysis.. The levels of cytokines IL-17, TNFα, IL-6 and IL-22 in RA group were significantly higher than those in the control group [(43 ± 6)ng/L, (5.91 ± 2.53)ng/L, (16.6 ± 12.0)ng/L, (51 ± 17)ng/L vs (21 ± 3)ng/L, (2.63 ± 0.27)ng/L, (4.2±2.3)ng/L, (22 ± 14)ng/L]. Each of the three different 1,25(OH)₂D₃doses inhibited secretion of IL-17[(533 ± 47) pg/ml, (426 ± 55)pg/ml, (319 ± 86)pg/ml], TNFα[(424 ± 82)pg/ml, (382 ± 79)pg/ml, (326 ± 87)pg/ml], and IL-6[(5 513 ± 3 429)pg/ml, (4 555 ± 3 157)pg/ml, (3 748 ± 1 919)pg/ml] in RA group (P < 0.05), yet no statistical difference was found in IL-22 secretion with a trend of decrease after treatment of 1,25(OH)₂D₃. Three different doses of MTX inhibited secretion of IL-17 [(452 ± 50) pg/ml, (372 ± 67) pg/ml, (315 ± 104)pg/ml] and TNFα [(319 ± 74)pg/ml, (292 ± 59)pg/ml, (266 ± 64)pg/ml] in RA group (P < 0.05).However, levels of IL-6 and IL-22 were not affected after treated with MTX.. Our data indicated that 1,25(OH)₂D₃may play as an immune modulating agent to suppress Th17 cell cytokines. Supplement of vitamin D has the effective potential to treat patients with RA or other Th17 cell mediated autoimmune disorders.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Case-Control Studies; Cholecalciferol; Cytokines; Dose-Response Relationship, Drug; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-17; Interleukin-22; Interleukin-6; Interleukins; Leukocytes, Mononuclear; Male; Methotrexate; Middle Aged; RNA, Messenger; Th17 Cells; Tumor Necrosis Factor-alpha; Vitamin D; Vitamins

A comprehensive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to quantify 10 forms of vitamin D in sera from healthy adults and patients suffering from rheumatoid arthritis (RA), type 1 diabetes (T1-D), and Alzheimer disease (AD).. The rapid assay, validated according to US Food and Drug Administration guidelines with Chromsystems and DEQAS samples, was applied to 36 nonhealthy sera samples (41.7% male, age range of 14-95, mean = 54.00 ± 21.98 years), consisting of individuals with RA, T1-D, and AD (n = 12 each) and was compared to samples from 32 healthy individuals (50% male, age range of 19-90, mean = 58.83 ± 22.93 years).. The key findings are (1) the 23R,25-dihydroxyvitamin D3 form was quantified for the first time (healthy = 0.427 ± 0.633 nmol/L; combined disease = 0.395 ± 0.483 nmol/L), (2) the 3-epi-25-hydroxyvitamin D3 metabolite was found in all groups with significantly higher concentration in the diseased samples [healthy = 6.093 ± 6.711 nmol/L; combined disease = 22.433 ± 13.535 nmol/L, t(52.5) = -6.411; P < .001], (3) a significant difference was found for the active form (1α-25-dihydroxyvitamin D3) between health (0.027 ± 0.035 nmol/L) and disease (0.433 ± 0.870 nmol/L) [t(35.1) = -2.797, P = 0.008], and (4) there was no significant correlation between the total circulating and total active forms in either the disease or healthy group (r = -0.180 and -0.274, respectively, with no difference between the correlation coefficients, z = -0.389, P = .697). Receiver operating characteristic curve analysis showed good sensitivity and specificity for using the 3-epi-25-hydroxyvitamin D concentration to predict disease status (area under the curve = 0.880, P < .001). Discriminant function analysis using concentrations of 23R,25-dihydroxyvitamin D3, 25-hydroxyvitamin D2, and 3-epi-25-hydroxyvitamin D classified 94.4% (91.7% in cross-validation) of the cases correctly.. This study reveals significant differences between health and disease with epimers having the potential to relate to disease. The potential implications of the information gleaned from measuring all forms warrant application of more comprehensive assays for future clinical studies investigating the link between vitamin D and health.

Topics: 25-Hydroxyvitamin D 2; Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Arthritis, Rheumatoid; Calcifediol; Chromatography, Liquid; Diabetes Mellitus, Type 1; Female; Humans; Male; Middle Aged; Tandem Mass Spectrometry; Vitamin D; Young Adult

Receptor activator of nuclear factor κ B ligand (RANKL) plays a crucial role in the bone erosion of rheumatoid arthritis (RA) by prompting osteoclastogenesis. Considering that 1,25(OH)2D3 has been suggested as a potent inducer of RANKL expression, it should clarify whether vitamin D supplement could result in RANKL overexpression and thereby facilitate excessive osteoclastogenesis and bone resorption in RA. Here, we investigated modulatory effect of 1,25(OH)2D3 on the expression of RANKL and its decoy receptor osteoprotegerin (OPG) in an inflammatory condition of human rheumatoid synoviocyte MH7A. MH7A cells were stimulated with IL1 β and then treated with different concentrations of 1,25(OH)2D3 for 48 h. A significantly elevated OPG/RANKL ratio and markedly decreased levels of IL-6 and TNF β mRNA expression in cells and IL-6 protein in supernatants were observed in IL1 β -induced MH7A in the presence of 1,25(OH)2D3 compared with those in the absence of it. Osteoclast formation was obviously decreased when RAW264.7 cells were treated with both 1,25(OH)2D3 and IL1 β . In summary, although it has a biological function to induce RANKL expression, 1,25(OH)2D3 could upregulate OPG/RANKL ratio and mediate anti-inflammatory action in an inflammatory milieu of synoviocyte, contributing to the inhibition of inflammation-induced osteoclastogenesis in RA.

Topics: Animals; Arthritis, Rheumatoid; Bone Resorption; Cell Line; Dose-Response Relationship, Drug; Fibroblasts; Gene Expression Regulation; Humans; Interleukin-1beta; Interleukin-6; Mice; Osteoclasts; Osteoprotegerin; RANK Ligand; Synovial Membrane; Tumor Necrosis Factor-alpha; Vitamin D

Topics: Adrenal Cortex Hormones; Arthritis, Rheumatoid; Humans; Interleukin-10; Interleukin-17; Osteoporosis; T-Lymphocyte Subsets; Vitamin D

The present study determined the levels in synovial fluid (SF) of vitamin D metabolites (1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D) and 25-hydroxyvitamin D (25-OH-D)), and of the cytokines. We evaluated SF from 21 patients with rheumatoid arthritis (RA) and 6 patients with osteoarthritis (OA). The levels of vitamin D metabolites in SF, as determined by two different extraction methods, were significantly correlated (p < 0.05, n=7). The levels of 3 vitamin D metabolites were significantly higher in the RA SF than in OA SF (p < 0.05). The ratio of 1,25(OH)2D/25-OH-D in RA SF, which is presumed to reflect the activity of 25-OH-D-1-hydroxylase (1-OH-ase), was positively correlated with the levels of interleukin-1alpha (IL-1alpha), IL-1beta, and IL-2 in such SF, and was significantly higher than that in sera from RA patients. This suggests an important role for these cytokines in the activation of 1-OH-ase in RA synovium. The ratio of 24,25(OH)2D/25-OH-D, which is presumed to reflect 25-OH-D-24-hydroxylase (24-OH-ase) activity, was significantly correlated with 1,25(OH)2D levels only in RA SF, but not in sera from RA patients, suggesting a local regulation of vitamin D metabolism that 1,25-(OH)2D induces 24-OH-ase as in other target cells. Our observations suggested that 1,25(OH)2D and 24,25(OH)2D are produced locally from 25-OH-D in RA synovium, and that the syntheses of 1,25(OH)2D and 24,25(OH)2D may be affected by IL-1/IL-2 and 1,25(OH)2D in RA SF, respectively.

Topics: Arthritis, Rheumatoid; Humans; Interleukin-1; Interleukin-2; Synovial Fluid; Vitamin D